BACKGROUND: The combination of ibrutinib and venetoclax leverages complementary mechanisms of action and has shown promising clinical activity in mantle cell lymphoma (MCL). This study evaluated the efficacy and safety of ibrutinib-venetoclax compared with ibrutinib-placebo in patients with relapsed or refractory MCL. METHODS: SYMPATICO is a multicentre, randomised, double-blind, placebo-controlled, phase 3 study performed at 84 hospitals in Europe, North America, and Asia-Pacific. Eligible patients were adults (aged ≥18 years) with pathologically confirmed relapsed or refractory MCL after one to five previous lines of therapy and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients were randomly assigned (1:1) to receive oral ibrutinib 560 mg once daily concurrently with oral venetoclax (5-week ramp-up to 400 mg once daily) or placebo for 2 years, then single-agent ibrutinib 560 mg once daily until disease progression or unacceptable toxicity. Randomisation and treatment assignment occurred via interactive response technology using a stratified permuted block scheme (block sizes of 2 and 4) with stratification by ECOG performance status, previous lines of therapy, and tumour lysis syndrome risk category. Patients and investigators were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03112174, and is closed to enrolment. FINDINGS: Between April 26, 2018, and Aug 28, 2019, 267 patients were enrolled and randomly assigned; 134 to the ibrutinib-venetoclax group and 133 to the ibrutinib-placebo group. 211 (79%) of 267 patients were male and 56 (21%) were female. With a median follow-up of 51·2 months (IQR 48·2-55·3), median progression-free survival was 31·9 months (95% CI 22·8-47·0) in the ibrutinib-venetoclax group and 22·1 months (16·5-29·5) in the ibrutinib-placebo group (hazard ratio 0·65 [95% CI 0·47-0·88]; p=0·0052). The most common grade 3-4 adverse events were neutropenia (42 [31%] of 134 patients in the ibrutinib-venetoclax group vs 14 [11%] of 132 patients in the ibrutinib-placebo group), thrombocytopenia (17 [13%] vs ten [8%]), and pneumonia (16 [12%] vs 14 [11%]). Serious adverse events occurred in 81 (60%) of 134 patients in the ibrutinib-venetoclax group and in 79 (60%) of 132 patients in the ibrutinib-placebo group. Treatment-related deaths occurred in three (2%) of 134 patients in the ibrutinib-venetoclax group (n=1 COVID-19 infection, n=1 cardiac arrest, and n=1 respiratory failure) and in two (2%) of 132 patients in the ibrutinib-placebo group (n=1 cardiac failure and n=1 COVID-19-related pneumonia). INTERPRETATION: The combination of ibrutinib-venetoclax significantly improved progression-free survival compared with ibrutinib-placebo in patients with relapsed or refractory MCL. The safety profile was consistent with known safety profiles of the individual drugs. These findings suggest a positive benefit-risk profile for ibrutinib-venetoclax treatment. FUNDING: Pharmacyclics (an AbbVie Company) and Janssen Research and Development.
- MeSH
- Adenine * analogs & derivatives MeSH
- Bridged Bicyclo Compounds, Heterocyclic * administration & dosage therapeutic use adverse effects MeSH
- Progression-Free Survival MeSH
- Adult MeSH
- Double-Blind Method MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Recurrence, Local drug therapy pathology MeSH
- Lymphoma, Mantle-Cell * drug therapy pathology mortality MeSH
- Piperidines * administration & dosage MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use adverse effects MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Sulfonamides * administration & dosage therapeutic use adverse effects MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
BACKGROUND: Exercise capacity is well known to be an important prognostic factor in patients with cardiovascular disease and among healthy persons. AIM: To determine if there are any differences between the peak exercise response during exercise treadmill testing with the individualized ramp protocol and the modified Bruce protocol in elderly patients. MATERIALS AND METHODS: The study included 40 patients (both male and female), aged 70 years and older, who had not had a baseline history of the confirmed coronary artery disease or heart failure diagnoses. All patients underwent exercise treadmill testing using modified Bruce protocol and individualized ramp protocol for 2 consecutive days. Peak heart rate, peak systolic and diastolic blood pressure, peak pressure-rate double product, exercise duration, and peak metabolic equivalents were recorded in both tests. Perceived level of exertion was evaluated using the Borg 10-point scale. RESULTS: The average duration of exercise was longer for the ramp protocol than for the modified Bruce protocol. When the modified Bruce protocol was used, patients achieved a lower workload than they did in using the ramp protocol. The rating of perceived exertion using the revised Borg scale (0 to 10) was 5.6±1.4 for the ramp protocol and 8.7±1.4 for the modified Bruce protocol, which indicates that the patients found the ramp protocol easier. CONCLUSION: In elderly patients the individualized ramp treadmill protocol allows to achieve the optimal test duration with higher degrees of workload and greater patient comfort during the test more often than does the modified Bruce protocol.
- MeSH
- Blood Pressure * MeSH
- Humans MeSH
- Metabolic Equivalent MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Oxygen Consumption * MeSH
- Heart Rate * MeSH
- Physical Exertion MeSH
- Exercise Tolerance * MeSH
- Exercise Test methods MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Cíle: Cílem naší studie bylo zhodnotit vliv absolvované tøímìsíèní kardiovaskulární reha- bilitace (ambulantní øízený trénink, individuální domácí trénink) v II. fázi na toleranci zátìže u pacientek po prodìlaném infarktu myokardu. Vyšetøované osoby: Do retrospektivní studie bylo zaøazeno celkem 48 pacientek (vìk 61,15 ± 7,22 let), z nichž 24 pacientek tréninkového souboru absolvovalo ambulantní øízený trénink (vìk 61,54 ± 7,06 let) a 24 pacientek domácího souboru, které mìly individuální domácí trénink (vìk 60,75 ± 7,65 let). Metodika: Všech 48 pacientek absolvovalo vstupní a následnì po tøímìsíèním tréninku kardiovaskulární rehabilitace výstupní spiroergometrické zátìžové vyšetøení kontinuálním rampovým protokolem do subjektivního symptomy limitovaného maxima spolu s dosažením anaerobního prahu a respiratory exchange ratio nad 1,10. Byly hodnoceny parametry tolerance zátìže výkon (W), výkon vztažený na tìlesnou hmotnost (W/kg) a vrcholová aerobní kapacita (VO2peak). Výsledky: Tøímìsíèní ambulantní øízený trénink vedl u tréninkového souboru ke zlepšení tolerance zátìže, došlo k signifikantnímu zlepšení všech sledovaných parametrù, výkonu o 27,18 % z 91,38 W na 116,22 W, výkonu vztaženého na tìlesnou hmotnost o 28,57 % z 1,19 W/kg na 1,53 W/kg a vrcholové aerobní kapacity o 28,09 % z 15,52 ml/kg/min na 19,88 ml/kg/min. Naopak absolvování tøímìsíèního domácího tréninku nevedlo u domácího souboru ke zlepšení tolerance zátìže pacientek po infarktu myokardu, došlo dokonce k nesigni- fikantnímu zhoršení výkonu o 0,99 % z 98,83 W na 97,85 W, výkonu vztaženého na tìlesnou hmotnost o 0,76 % z 1,32 W/kg na 1,31 W/kg a vrcholové aerobní kapacity o 3,46 % z 17,65 ml/kg/min na 17,04 ml/kg/min. Porovnáním dosažených hodnot mezi obìma soubory byl zjištìn signifikantní rozdíl mezi výstupními hodnotami vybraných parametrù tolerance zá- tìže. Pacientky tréninkového souboru dosáhly oproti pacientkám domácího souboru signifi- kantnì vyšších výstupních hodnot výkonu o 18,77 %, výkonu vztaženého na tìlesnou hmotnost o 16,79 % a vrcholové aerobní kapacity o 16,67 %. Závìr: Z výsledkù naší studie lze usuzovat, že pro zlepšení tolerance zátìže u pacientek po infarktu myokardu je pro II. fázi kardiovaskulární rehabilitace vhodnìjší indikovat ambulantní øízený trénink v porovnání s edukací se samostatným domácím vykonáváním pohybového tré- ninku, které k ovlivnìní tolerance zátìže nevedou.
Aims: The aim of our study was to evaluate the effect of completed 3-month cardiovascular rehabilitation (outpatient controlled training, individual home-based training) in the 2nd phase on exercise tolerance in women after myocardial infarction. Persons examined: A total of 48 female patients (aged 61.15 ± 7.22 years) were included in the retrospective study, of which 24 female patients of training group underwent outpatient controlled training (aged 61.54 ± 7.06 years) and 24 female patients of home-based group who had individual home-based training (aged 60.75 ± 7.65 years). Methods: All 48 female patients underwent baseline and final spiroergometry exercise test- ing after 3-month training of cardiovascular rehabilitation with a continuous ramp protocol to a subjective symptoms limited maximum, along with anaerobic threshold and respiratory exchange ration above 1.10. Performance (W), body weight related performance (W/kg) and peak aerobic capacity (VO2peak) were evaluated. Results: The 3-month outpatient controlled training resulted in improved exercise tolerance and a significant improvement in all monitored parameters of training group - performance by 27.18%from91.38Wto 116.22W, bodyweight related performance by 28.57%from1.19W/kg to 1.53 W/kg and peak aerobic capacity by 28.09 % from 15.52 ml/kg/min to 19.88 ml/kg/min. Conversely, completing a 3-month home-based training did not lead to an improvement in exercise tolerance in female patients of home-based group after myocardial infarction, there was even an insignificant degradation of performance by 0.99 % from 98.83 W to 97.85 W, body weight related performance by 0.76%from 1.32 W/kg to 1.31 W/kg and peak aerobic ca- pacity by 3.46%from 17.65 ml/kg/min to 17.04 ml/kg/min. By comparing the achieved values between both groups, a significant difference was found between the final values of the selected parameters of exercise tolerance. Female patients of the training group achieved significantly higher final values of performance by 18.77 %, body weight related performance by 16.79 % and peak aerobic capacity by 16.67 % compared to female patients of the home-based group. Conclusion: From the results of our study it can be concluded, that for the improvement of the exercise tolerance in female patients after myocardial infarction it is more appropriate to indicate outpatient controlled training for the 2nd phase of cardiovascular rehabilitation compared to an education with independent home-based exercise training, which does not lead to influence the exercise tolerance.
- MeSH
- Ergometry MeSH
- Myocardial Infarction rehabilitation MeSH
- Cardiac Rehabilitation * methods MeSH
- Middle Aged MeSH
- Humans MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Spirometry MeSH
- Physical Exertion * MeSH
- Exercise Test MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
Kolísavý průběh dechového objemu (VT), dechové frekvence (DF) a minutové ventilace (VE) při spiroergometrickém vyšetření rampovým protokolem se vyskytuje nejen u nemocných, ale relativně často i u zdravých osob. Může vysvětlit řadu nepravidelností průběhu křivek příjmu kyslíku (VO2), výdeje oxidu uhličitého (VCO2) a zejména křivek ventilačních ekvivalentů pro O2 a CO2 (EQO2, EQCO2) a též křivek parciálních tlaků O2 a CO2 na konci výdechu (PETO2, PETCO2), které se používají mimo jiné i ke stanovení ventilačních prahů. Přítomnost oscilujícího dýchání při zátěži (EOV) odráží závažnost srdečního selhání a je nezávislým prediktorem zvýšené morbidity, kardiální i celkové mortality a náhlé smrti z kardiálních příčin. V současné době ale není k dispozici všeobecně akceptovaná univerzální definice EOV, užívají se různá kritéria. Nenašli jsme porovnání, zda a jak se liší „síla“ prognostického kritéria pro EOV stanoveného dle různých metod. Je proto velmi důležité uvést, jakou metodou, respektive podle jakých kritérií byla EOV stanovena.
The fluctuating course of tidal volume (VT), breathing frequency (DF) and minute ventilation (VE) during the cardiopulmonary exercise test using a ramp incremental protocol occurs not only in patients, but relatively frequently also in healthy individuals. It can account for a number of irregularities in the course of the curves VO2, VCO2 and in particular of those of ventilatory equivalents for O2 and CO2 (EQO2, EQCO2) as well as curves of partial pressure of end-tidal oxygen and partial pressure of end-tidal carbon dioxide (PETO2, PETCO2), which are also used, inter alia, to establish ventilatory thresholds. The presence of exercise oscillatory ventilation (EOV) reflects the severity of heart failure and it is an independent predictor of the increased morbidity, cardiac and total mortality and sudden death caused by heart failure. However there is not a generally accepted universal definition of EOV available at present, as different criteria are used. We have not found a comparison which would indicate whether and how the “strength” of the prognostic criteria for EOV – established according to different methods – differs. Therefore it is very important to specify what method, or what criteria were used in the establishment of EOV.
